Project 3: SUMMARY Children obesity, asthma and particulate matter (PM) exposure disproportionally affect low-income minority children in the US. Previous research from our group provided evidence that obesity may exacerbate effects of PM on asthma. The overall OBESE ASTHMA Program proposal focuses on the role of obesity in amplifying the pathogenic effects of PM on asthma in children. The underlying mechanisms by which obesity augments effects of PM are poorly understood. Our Preliminary Data show that obesity enhances PM-induced airway hyperresponsiveness (AHR) and increases IL-6 levels in the lungs. PM and obesity may interact leading to AHR and chronic airway inflammation. Obesity also predisposes to obstructive sleep apnea (OSA). OSA is highly associated with asthma in children and treatment of OSA improves asthma control. Environmental pollution is associated with OSA and reduction in air pollution decreases the severity of OSA. Thus, obesity and sleep apnea may interact with PM to exacerbate asthma. Animal studies of Project 3 will complement human Projects 1 and 2 enabling us to examine these relationships mechanistically. We will 1) utilize established models of diet-induced obesity (DIO) and PM exposure in the non-atopic obesity-prone mouse strain C56BL/6J to identify the effect of obesity on the AHR; 2) examine the role of adipokines and inflammatory cytokines, especially IL-6; 3) examine the role of sleep apnea using our novel model of upper airway obstruction during sleep induced by excessive tongue adiposity; this unique model has been engineered by overexpressing an adipogenic transcription factor peroxisome proliferator-activated receptor gamma(PPAR?) in the tongue. The overarching hypothesis of the Project 3 is that obesity exacerbates the PM-induced AHR due to pathogenic effects of adiposity and comorbid sleep apnea and that the effects of obesity are mediated via IL-6. Furthermore, these detrimental effects of obesity can be attenuated by weight loss and sleep apnea treatment. In Specific Aim 1, we will test causal links between obesity and the PM-induced AHR and inflammation. (A) We will quantify the PM-induced AHR and inflammation in lean and DIO wildtype and IL-6 knockout mice; (B) To link to potential therapeutic actions, we will quantify the ability of weight loss to attenuate the PM-induced AHR and inflammation. In Specific Aim 2, we will examine effects of sleep apnea on the PM-induced AHR and inflammation. We will quantify the PM- induced AHR and inflammation in DIO mice with recurrent upper airway obstruction during sleep caused by genetically induced excessive tongue adiposity. Experiments will also assess the effects of sleep apnea treatment, which will be modelled by supplemental oxygen. Thus, Project 3 will complement human studies proposed in Projects 1 and 2 exploring the causal relationships between PM, obesity and sleep apnea in the development of AHR and airway inflammation.